Novel anti-infectious derivatives, method for the production thereof, pharmaceutical compositions containing same and uses of said derivatives in treatment

ABSTRACT

The invention relates to bi-substrate inhibitor molecules associating (i) a pyridine, pyridinium or dihydropyridine-type structure allied to active metabolites of isoniazide, or related structures, and (ii) a hydrophobic substituent. The invention also relates to the method for producing said molecules, to the pharmaceutical compositions containing said molecules, and to the use thereof as inhibitors of enoyl reductase for the preparation of a medicament, especially an anti-infectious medicament for the treatment of tuberculosis.

The present invention relates to bi-substrate inhibitor moleculescombining a hydrophobic substituent with an analogue of the activemetabolite of isoniazide, to the method for the preparation thereof, topharmaceutical compositions containing them, and to the use thereof, inparticular as enoyl-ACP (acyl carrier protein) reductase inhibitors, forthe preparation of an anti-infective drug, in particular anantituberculous drug.

In the fight against infectious diseases, the medical profession isconstantly seeking new active molecules for effectively combating thecrucial problem of resistance. In this respect and by way of example,the treatment of tuberculosis, a disease which has undergone a verydisconcerting worldwide revival over the last twenty years or so, posesthe problem of replacing the current front-line antibiotics, theefficacy of which has been greatly affected by the resistance developedby the germ responsible for this illness.

The invention is based on rationally designing new compounds on thebasis of an improved knowledge of the mechanism of action of a referencedrug and of resistance mechanisms.

The fatty acid elongation system (fatty acid synthase II or FAS-IIsystem) is necessary for the biosynthesis of mycolic acids, specificconstituents and essential components of the envelope of mycobacteria,in particular Mycobacterium tuberculosis (or Koch's bacillus), thepathogen for tuberculosis, M. leprae, the pathogen for leprosy, andother mycobacteria which are opportunistic pathogens (for example M.avium, M. ulcerans, M. marinum). This potential therapeutic target isalso found in some other infectious agents (for example Plasmodiumfalciparum, the parasite responsible for malaria).

Isoniazide (INH) is a front-line antituberculous antibiotic, theefficacy of which is increasingly being limited by the appearance ofnew, resistant strains of M. tuberculosis. It is a pro-drug which isactivated by oxidation in the mycobacterium due to a catalase peroxidase(KatG), forming covalent isonicotinoyl-NAD (INH-NAD) adducts consideredto be the active metabolites of isoniazide. These adducts are excellentinhibitors of InhA, an enzyme in the FAS-II system. Analogous adducts,isonicotinoyl-NADP (INH-NADP), also inhibit another enzyme in the FAS-IIsystem, the protein MabA, which has a 3D structure related to that ofInhA. The resistance phenomena which occur are largely due to mutationswhich principally affect the KatG enzyme (lack of activation). Mutationsare also similarly encountered, in a smaller proportion, in the targetenzyme InhA (loss of affinity of the inhibitor adduct for its target invivo) or its promoter (overproduction of the target). Designingbi-substrate inhibitors which do not require a prior activation step byway of KatG, and which ideally interact within the InhA active site withregions of the protein which exclude the most frequently encounteredmutation sites, should make it possible largely to overcome the currentproblems of INH resistance.

The present inventors have therefore developed bi-substrate InhAinhibitors combining (i) a unit derived from the active metabolites ofisoniazide of the pyridine, pyridinium or dihydropyridine type andrelated structures, and (ii) a hydrophobic substituent targeting thesite of the substrate.

Whilst not limited by theory, the compounds identified by the presentinvention also have other targets and exhibit inhibitory propertiestowards bacterial strains without an InhA equivalent, making themanti-infective compounds having a wide range of applications.

The present invention relates to compounds of general formula (I):

in the form of a base or an acid addition salt, as well as in the formof a pharmaceutically acceptable hydrate or solvate,in which:

-   -   the cycle

represents a 6-membered aromatic or non-aromatic ring, optionallycomprising one or more nitrogen atoms, said nitrogen atom(s) optionallybeing substituted byan optionally substituted tetrahydrofuran group, such as2-hydroxymethyl-tetrahydrofuran-3,4-diol; or bya —CH₂-E group, wherein E represents an electron-attracting group suchas —CONRR′; —CO—SR; phenyl substituted for example by a CN or NO₂ group;—CO—Oalkyl; —CO—Oalkyl-OH; —O-alkyl-OAc; wherein R and R′ are the sameor different and independently represent a hydrogen atom or an alkylgroup;more preferably, the nitrogen atom is optionally substituted by a groupselected from the groups —CH₂—CO—Oalkyl; —CH₂—CO—Oalkyl-OH;—CH₂—O-alkyl-OAc;and/or wherein said nitrogen atom(s) may be in the form of pyridiniumsalts, the counter ion being the anion of a halogen atom, such asbromide or another pharmaceutically acceptable anion.

Preferably,

is an optionally substituted phenyl, pyridine, pyrazine ordihydropyridine ring.

More preferably,

represents a dihydropyridine or pyridine group, optionally substitutedby a group selected from the groups —CH₂—CO—Oalkyl, —CH₂—CO—Oalkyl-OH,—OH₂—O-alkyl-OAC, and/or optionally in the form of a pyridinium halide;

represents a 5-to-10-membered mono- or bicyclic aryl or heteroarylgroup, substituted by one or more groups selected from the groups —OH;—(C₅-C₂₀)alkyl; —O(C₂-C₂₀)alkyl; —S(O)_(p)alkyl wherein p=0, 1 or 2;alkenyl; alkynyl; —Oalkenyl; —C(═)O-alkyl; —C(═O)-alkenyl; phenylsubstituted by an alkyl group; cycloalkyl optionally substituted by analkyl group.

Preferably,

is a phenyl ring substituted by one or more groups selected from thegroups —OH; —(C₅-C₂₀)alkyl; —O(C₅-C₂₀)alkyl; —S(O)_(p)(C₅-C₂₀)alkylwherein p=0, 1 or 2; (C₅-C₂₀)alkenyl; (C₅-C₂₀)alkynyl;—O(C₅-C₂₀)alkenyl; —C(═)O—(C₅-C₂₀)alkyl; —C(═O)—(C₅-C₂₀)alkenyl; phenylsubstituted by a (C₅-C₂₀) alkyl group; and cycloalkyl optionallysubstituted by an alkyl group.

More preferably,

is a phenyl ring substituted by a —OH, (C₅-C₂₀)alkyl, O(C₅-C₂₀)alkenyl,O(C₅-C₂₀)alkyl or —S(O)_(p)alkyl group wherein p=0, 1 or 2.

More preferably,

is substituted in the ortho or meta position;

-   -   R1 represents a hydrogen atom or an alkyl group and R2 and R3        together form an ═O group;        or alternatively        R3 represents an —OH or —Oalkyl group and R2 forms, together        with R1, a single bond binding the nitrogen atom to the carbon        atom substituted by R3,

in such a way as to form an indanone ring by fusion with the cycle

Preferably, R3=OH or —Oalkyl and R1 and R2 together form a single bond,or R3 and R2 form an ═O group and R1 represents a hydrogen atom.

In the above and in the following, the groups —C(═O)NHR1 and C(R3)(R2)-are understood to be located in two adjacent positions on the ring

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may therefore exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers and themixtures thereof, including racemic mixtures, are part of the invention.

The compounds of formula (I) may exist in the form of bases or acidaddition salts. Addition salts of this type are part of the invention.

These salts can be prepared with pharmaceutically acceptable acids, butthe salts of other acids which can be used, for example, for thepurification or isolation of the compounds of formula (I) are also partof the invention.

The compounds of formula (I) may also exist in the form of hydrates orsolvates, namely in the form of associations or combinations with one ormore water molecules or with a solvent. Hydrates and solvates of thistype are also part of the invention.

In the context of the present invention:

-   -   halogen atom means a fluorine, chorine, bromine or iodine;    -   alkyl group means a linear or branched saturated aliphatic group        having 1 to 20 carbon atoms, unless stated otherwise. Examples        include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and        tert-butyl groups;    -   cycloalkyl group means a cyclic alkyl group having 3 to 10        carbon atoms. Examples include cyclopropyl, methylcyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl etc.;    -   alkenyl group means a linear or branched, mono- or        polyunsaturated aliphatic group of 2 to 20 carbon atoms,        comprising for example one or two ethylenic unsaturations;    -   alkynyl group means a linear or branched, mono- or        polyunsaturated aliphatic group of 2 to 20 carbon atoms,        comprising for example one or two acetylenic unsaturations;    -   aryl group means a cyclic aromatic group comprising between 5        and 10 carbon atoms. Examples of aryl groups include phenyl and        naphthyl;    -   heteroaryl group means a cyclic aromatic group comprising        between 5 and 10 carbon atoms and comprising between 1 and 3        heteroatoms, such as nitrogen, oxygen or sulphur. Examples of        heteroaryl groups include pyridine in particular.

Compounds of formula (I) are particularly preferred in which:

represents a dihydropyridine group, optionally substituted by a groupselected from —CH₂COOalkyl, —CH₂COOalkylOH;

represents a phenyl group, substituted in the ortho or meta position,preferably the meta position, by a group selected from the groups C₅-C₂₀alkyl, —Oalkyl, —Oalkenyl, —OH, phenyl optionally substituted by alkyl;

R1 and R2 together form a single bond and R3=OH, or R1=H and R2 and R3together form an ═O group;

in the form of a base or an acid addition salt, as well as in the formof a pharmaceutically acceptable hydrate or solvate.

Compounds of formula (I) according to the invention include inparticular the following compounds:

-   1-(3-dodecylphenyl)-1-hydroxy-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;-   1-(3-dodecyloxyphenyl)-1-hydroxy-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;-   1-(3-dodecylphenyl)-5-[2-(ethyloxy)-2-oxoethyl]-1-hydroxy-3-oxo-1,2-dihydropyrrolo[3,4-c]pyridinium    bromide;-   ethy    3-aminocarbonyl-[4-(3-dodecylbenzoyl)-1,4-dihydro-pyridin-1-yl]acetate;-   1-(3-octyloxyphenyl)-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;-   1-(2-dodecyloxyphenyl)-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;-   1-(3-octodecyloxyphenyl)-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;-   1-[3-(dodecylthio)phenyl]-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;-   1-(3-dodecyloxyphenyl)-1-methoxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;-   1-hydroxy-1-(3-(propen-3-yl)oxyphenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;-   1-hydroxy-1-(3-hydroxyphenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;-   1-hydroxy-1-(3-octylphenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;-   1-hydroxy-1-(3-(4-nonylphenyl)phenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;-   1-[3-(dodecyloxy)phenyl]-5-(2-ethoxy-2-oxoethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-5-ium    bromide;-   1-[(3-(dodecyloxy)phenyl)-1-hydroxy-5-[2-(3-hydroxypropoxy)-2-oxyethyl]-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-5-ium    bromide;-   ethyl    3-aminocarbonyl-[4-(3-dodecyloxybenzoyl)-1,4-dihydropyridin-1-yl]acetate;-   3-hydroxypropyl    3-aminocarbonyl-[4-(3-dodecyloxybenzoyl)-1,4-dihydropyridin-1-yl]acetate;    in the form of a base or an acid addition salt, as well as in the    form of a pharmaceutically acceptable hydrate or solvate.

The present application further relates to the method for thepreparation of compounds of general formula (I).

According to the invention, the compounds of general formula (I) can beprepared by the following method.

More precisely, in a first embodiment, the compounds of general formula(I) in which R1 and R2 together form a single bond and R3 represents —OHcan be prepared by coupling a compound of general formula (II):

and a compound of general formula (III):

resulting in a compound of formula (IV):

in which

and R1 are defined as in general formula (I), Hal represents a halogenatom and X represents a hydrogen atom, when

is not substituted, or the substituent of

corresponding to the desired general formula (I) (in these two cases,the compound (IV) corresponds to the compound (I)), or a halogen atom,the coupling being followed in this case by the reaction substitutingthe halogen atom of the compound (IV) with the appropriate substituentof

corresponding to the desired general formula (I).

The coupling reaction generally takes place in the presence of anorganic or inorganic base such as n-BuLi or t-BuLi, in a solvent such asTHF, at a temperature between −78° and ambient temperature, in an inertatmosphere.

The substitution reaction is generally carried out by applying oradapting substitution reactions known to the person skilled in the art,using appropriate reagents. These substitution reactions are describedfor example in March's Advanced Organic Chemistry, 5^(th) Ed., JohnWiley and Sons, Inc. or Larock, Comprehensive Organic Transformations,VCH Ed. A representative example is the substitution reaction resultingin the compound of general formula (I) in which

is substituted by an alkyl group. This reaction may in particular becarried out using alkylboronic acid in the presence of diphenylphosphinoferrocene palladium (II) chloride, silver oxide and potassium carbonate.

The compound of general formula (II) is commercially available or may beprepared by applying or adapting known methods for substituting the ring

as desired to obtain the compound of formula (I) in which

is substituted. For example, the ring

may be substituted by an Oalkyl group using a corresponding startingmaterial (II) in which

is substituted by a hydroxy group, by reacting a compound of the alkylhalide type in the presence of a base such as potassium carbonate.

According to a second embodiment, the compounds of general formula (I)in which R1 and R2 together form a single bond and R3 represents —OH maybe prepared by cyclising compounds of general formula (V):

in which

and Hal are defined as in general formula (IV) in the presence of NHR1(V′),resulting in the compound of formula (IV):

in which R1 is defined as in general formula (I) and X represents ahydrogen atom, when

is not substituted, or the substituent of

corresponding to the desired general formula (I) (in these two cases,the compound (IV) corresponds to the compound (I)), or a halogen atom,the cyclisation being followed in this case by the reaction substitutingthe halogen atom of the compound (IV) with the appropriate substituentof

corresponding to the desired general formula (I).

The cyclisation reaction is generally carried out using thionyl chlorideto form the corresponding acyl chloride, followed by the addition of acompound (V′) of formula

NHR1  (V′)

This reaction is generally carried out without intermediate isolation ofthe acyl chloride, at a temperature between ambient temperature and theboiling point of the reaction mixture.

The compound of formula (V′) may in particular be ammonium hydroxidedissolved in water.

The substitution reaction is generally carried out as discussed above.

The compound of formula (V) may be obtained from a compound of formula(VI):

in which

and X are defined as in general formula (V). This reaction is generallycarried out in an acidic medium, for example in formic acid, at atemperature between ambient temperature and the reflux temperature ofthe reaction mixture.

The compound of formula (VI) may be obtained by reduction of thecorresponding compound of formula (VII):

in which

and X are defined as in general formula (VI). This reaction cangenerally be carried out using a reducing agent such as sodiumtetraborohydride, in a solvent such as an alcohol, for example ethanol.

The compound of formula (VII) can be prepared by coupling correspondingcompounds of formulae (VIII) and (IX):

in which

and X are as defined in general formula (VII) and Alk and Alk′ are thesame or different and independently represent an alkyl group. Thisreaction is generally carried out in the presence of a base such as alithium-based compound, for example lithium diisopropylamide, in anappropriate organic solvent, such as diethyl ether. This reaction ispreferably carried out in an anhydrous medium, in an inert atmosphere,by adding the base to the compound of formula (IX) and then adding thecompound of general formula (VIII). This reaction is preferably carriedout at a temperature between −75° C. and 0° C.

The compound of formula (VIII) may be obtained by coupling correspondingcompounds of formulae (X) and (XI):

in which

X, Alk and Alk′ are defined as in general formula (VIII). This reactionis generally carried out using coupling reagents of the EDCI type, suchas 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (hydrochloride salt),and of the HOBT type (1-hydroxy-1H-benzotriazole hydrate) and in thepresence of a base such as triethylamine.

When

represents a pyridinium ring in which the nitrogen atom is quaternised,the preparation method further comprises the step of quaternising thecompound of general formula (I) in which

represents a pyridine ring using a compound of general formula (XII):

R-Hal  (XII)

in which Hal represents a halogen atom, such as bromine, and Rrepresents a group of the —CH₂E type, E being an electron-attractinggroup defined as in general formula (I). This reaction is generallycarried out in a solvent such as anhydrous tetrahydrofuran, at atemperature between ambient temperature and the reflux temperature ofthe reaction mixture.

When

represents a dihydropyridine ring and R2 and R3 together form an ═Ogroup and R1 represents a hydrogen atom, the compound of general formula(I) can be obtained by reduction from the compound of general formula(I) in which

represents a pyridinium ring. The reducing agent may in particular besodium triacetoxyborohydrate in an acetic medium. This reaction isgenerally carried out at a temperature between −10° C. and ambienttemperature.

Diagram 1 below illustrates the method according to the invention.

The method according to the invention optionally comprises thesubsequent step of isolating the desired product obtained.

The starting materials (II), (III), (IX), (X), (XI) and the appropriatereagents are commercially available or may be prepared by applying oradapting methods known to the person skilled in the art.

The compounds according to the invention have noteworthy anti-infectiveproperties.

According to a further aspect therefore the invention relates to drugscomprising a compound of formula (I)

in which:

-   -   the cycle

represents a 6-membered aromatic or non-aromatic ring, optionallycomprising one or more nitrogen atoms, said nitrogen atom(s) optionallybeing substituted byan optionally substituted tetrahydrofuran group, such as2-hydroxymethyl-tetrahydrofuran-3,4-diol; or bya —CH₂-E group, wherein E represents an electron-attracting group suchas —CONRR′; —CO—SR; —CO—Oalkyl; —CO—Oalkyl-OH; —O-alkyl-OAc; phenylsubstituted for example by a CN or NO₂ group; wherein R and R′ are thesame or different and independently represent a hydrogen atom or analkyl group;and/or wherein said nitrogen atom(s) may be in the form of pyridiniumsalts, the counter ion being the anion of a halogen atom, such asbromide;

represents a 5-to-10-membered mono- or bicyclic aryl or heteroarylgroup, substituted by one or more groups selected from the groups —OH;—(C₅-C₂₀)alkyl; —Oalkyl; —S(O)_(p)alkyl wherein p=0, 1 or 2; alkenyl;alkynyl; —Oalkenyl; —C(═)O-alkyl; —C(═O)-alkenyl; phenyl optionallysubstituted by an alkyl group; cycloalkyl optionally substituted by analkyl group;

-   -   R1 represents a hydrogen atom or an alkyl group and R2 and R3        together form an ═O group;        or alternatively        R3 represents an —OH or —Oalkyl group and R2 forms, together        with R1, a single bond binding the nitrogen atom to the carbon        atom substituted by R3,

in such a way as to form an indanone ring by fusion with the cycle

the groups —C(═O)NHR1 and C(R3)(R2)- being understood to be located intwo adjacent positions on the ring

in the form of a base or an acid addition salt, as well as in the formof a pharmaceutically acceptable hydrate or solvate;and at least one pharmaceutically acceptable excipient.

Thus, the compounds according to the invention can be used asanti-infective agents in humans or animals, in particular in thetreatment or prevention of:

-   -   mycobacterioses, in particular tuberculosis, leprosy or        opportunistic diseases, such as those caused by Mycobacterium        avium, M. bovis, M. marinum and/or M. ulcerans;    -   malaria;    -   any infection caused by a pathogen having an enzyme of the enoyl        acyl carrier protein reductase type or an enzyme of a related        structure, belonging to the short chain dehydrogenase reductase        (SDR) superfamily.

More preferentially, the compounds according to the invention may beused in the treatment of tuberculosis.

According to a further aspect the present invention relates topharmaceutical compositions comprising a compound according to theinvention as an active ingredient. These pharmaceutical compositionscontain an effective dose of at least one compound according to theinvention, or a pharmaceutically acceptable salt, a hydrate or solvateof said compound, as well as at least one pharmaceutically acceptableexcipient.

Said excipients are selected from the conventional excipients known tothe person skilled in the art in accordance with the desiredpharmaceutical form and delivery system.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive ingredient of formula (I) above, or possibly the salt, solvate orhydrate thereof, may be administered to animals and to humans in aunitary administration form, in a mixture with conventionalpharmaceutical excipients, for the prophylaxis or treatment of the abovedisorders or diseases.

The appropriate unitary administration forms comprise oral forms such astablets, hard or soft capsules, powders, granules and oral solutions orsuspensions, sublingual, buccal, intratracheal, intraocular andintranasal administration forms, inhalation, topical, transdermic,subcutaneous and intramuscular or intravenous administration forms,rectal administration forms and implants. For topical application, thecompounds according to the invention can be used in creams, gels,ointments or lotions.

The pharmaceutical compositions according to the invention may comprise10 to 800 mg of a compound of general formula (I) according to theinvention as an active ingredient.

For example, a unitary administration form of a compound according tothe invention in the form of a tablet may comprise the followingingredients:

Compound according to the invention 50.0 mg Mannitol 224 mgCroscarmellose sodium 6.0 mg Maize starch 15.0 mg Hydroxypropylmethylcellulose 2 mg Magnesium stearate 3.0 mg

The dosage of active ingredient administered each day may amount to 0.01to 100 mg/kg, in one or more doses, preferably 0.02 to 50 mg/kg.

There may be particular cases where higher or lower dosages areappropriate; dosages of this type do not depart from the scope of theinvention. In conventional practice, the appropriate dosage for eachpatient is determined by the doctor in accordance with the deliverysystem and the weight and the response of said patient.

The present invention also further relates to combinations of a compoundof general formula (I) according to the invention and an anti-infectiveactive ingredient. Examples of anti-infective compounds include inparticular isoniazide, rifampicine, pyrazinamide, ethambutol,chloroquine, and any other antibiotic molecule in current clinical use.

The following examples disclose the preparation of particular compoundsaccording to the invention. These examples are non-limiting and merelyillustrate the present invention. The numbers of the example compoundscorrespond to those given in the table hereinafter, which illustratesthe chemical structures and the physical properties of some compoundsaccording to the invention.

All of the solvents used are of “reagent grade” or “HPLC grade” purity.

The present invention also relates to the method for preparing theaforementioned molecules of general formula (I).

The present invention also further relates to the use of the compoundsof general formula (I) in therapeutics.

The following examples are given for illustrative purposes and do notlimit the present invention.

Preparation 1: Synthesis of Compound 1 of Formula

Step 1: Synthesis of a Compound (1a)

Compound 1a has the following formula:

Triethylamine (2.9 ml, 19.3 mmol) is added dropwise, in an inertatmosphere, to a suspension of 3-bromobenzoic acid (4.0 g, 20.0 mmol),N,O-dimethylhydroxylamine hydrochloride (2.0 g, 21.0 mmol),1-hydroxy-1H-benzotriazole hydrate (920 mg, 6.0 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.6 g, 24.0 mmol) inanhydrous acetonitrile (25 ml). After 2 h of stirring at ambienttemperature, 20 ml of distilled water are added to the reaction mixture,and then the solvent is evaporated at a reduced pressure. The residue istaken up by the water and extracted with ethyl acetate (3×20 ml). Theorganic phases are combined, dried over anhydrous sodium sulphate, andconcentrated on a rotating evaporator yielding 4.7 g (98%) of amide 1ain the form of a pale yellow oil.

IR (film, cm⁻¹): 3066, 2969, 2934, 1644, 1383, 1211, 662. NMR ¹H (250MHz, CDCl₃) δ (ppm): 7.80 (t, 2H), 7.61-7.54 (m, 2H), 7.26 (t, 1H), 3.53(s, 3H), 3.34 (s, 3H). NMR ¹³C (50 MHz, CDCl₃) δ (ppm): 168.0, 135.6,133.4, 131.0, 129.4, 126.6, 121.8, 61.0, 33.4. HR-MS (FAB) forC₉H₁₁NO₂Br: observ. 243.9969, theor. 243.9973.

Step 2: Synthesis of a Compound (1b) Having a DiisopropylnicotinamideRing Comprising a 3-bromobenzoyl Radical in the 4 Position

Compound 1b has the following formula:

Lithium diisopropylamide (2.7 ml, 5.4 mmol, 2M in solution inTHF/n-heptane) is added dropwise, at −78° C., in an inert atmosphere, toa solution of N,N-diisopropylnicotinamide (618 mg, 3.0 mmol) inanhydrous diethyl ether (75 ml). After 20 minutes of stirring at −50°C., a solution of Weinreb amide 1a (1.1 g, 4.5 mmol) in anhydrousdiethyl ether (8 ml) is added dropwise at −78° C. 8 times, every 10minutes. The reaction medium is left to return to ambient temperaturewhile stirring and the reaction is followed by CCM (eluent:dichloromethane/methanol: 95/5). Subsequently, 50 ml of distilled waterare added to the solution, and the reaction mixture is extracted withethyl acetate (4×20 ml). The organic phases are combined, washed with asaturated sodium chloride solution, dried over anhydrous sodium sulphateand concentrated on a rotating evaporator. The oily residue obtained ispurified by chromatography in a silica gel column (eluent:dichloromethane/methanol gradient from 100/0 to 98/2), yielding 330 mg(28%) of the ketoamide 1b in the form of a yellow solid.

P_(f): 112° C. IR (KBr, cm⁻¹): 3061, 2971, 2933, 1675, 1630, 1343, 1267,668. NMR ¹H (250 MHz, CDCl₃) δ (ppm): 8.71 (d, 1H), 8.63 (s, 1H), 7.94(t, 1H), 7.73-7.66 (m, 2H), 7.32 (t, 1H), 7.30 (d, 1H), 3.87-3.77 (m,1H), 3.52-3.41 (m, 1H), 1.38 (d, 6H), 1.22 (d, 6H). NMR ¹³C (63 MHz,CDCl₃) δ (ppm): 193.5, 166.4, 149.4, 146.9, 143.6, 137.4, 133.6, 122.8,136.5, 132.6, 130.1, 128.8, 122.2, 51.7, 42.4, 20.5, 20.0. HR-MS (ESI)for C₁₉H₂₂N₂O₂Br: observ. 389.0864; theor. 389.0865.

Step 3: Reduction of the Carbonyl Function of the Amidoketone 1bObtained in Step 2

Sodium tetraborohydride (421 mg, 8.8 mmol) is added to a solution ofketoamide 1b (627 mg 1.6 mmol) in absolute ethanol (80 ml). After 3 h ofstirring at ambient temperature, 50 ml of distilled water are added. Thereaction mixture is extracted with dichloromethane (3×20 ml). Theorganic phases are combined, dried over anhydrous sodium sulphate andconcentrated on a rotating evaporator, yielding 631 mg (85%) of the tworotamers of the hydroxyamide 1c in the form of a yellow paste.

The two rotamers are obtained in the proportion 65/35, but forconvenience, the ¹H and ¹³C spectra are described as if the protons orcarbons of the minority rotamer had the same intensity as the protons orcarbons corresponding to the majority rotamer.

IR (KBr, cm⁻¹): 3243, 2973, 2934, 1615, 1443, 1344, 671. NMR ¹H (250MHz, CDCl₃) δ (ppm): 8.66 (d, 1H), 8.56 (d, 1H), 8.44 (s, 1H), 8.40 (s,1H), 7.45-7.43 (m, 4H), 7.36 (d, 2H), 7.29-7.10 (m, 4H), 6.02 (s, 1H),5.98 (s, 1H), 5.66 (s, 1H), 5.62 (s, 1H), 3.54-3.40 (m, 2H), 3.35-3.24(m, 2H), 153 (d, 6H), 1.41 (d, 3H), 1.27 (d, 3H), 1.20 (d, 3H), 1.14 (d,3H), 0.79 (d, 3H), 0.49 (d, 3H). NMR ¹³C (63 MHz, CDCl₃) δ (ppm): 169.1,168.1, 150.8, 150.4, 147.5, 145.6, 145.0, 143.5, 134.9, 134.2, 131.9,131.8, 126.0, 125.5, 131.2, 130.9, 130.3, 130.0, 129.1, 126.5, 125.1,124.8, 122.8, 121.8, 75.1, 70.7, 51.5, 51.4, 46.6, 46.4, 20.7, 20.6,20.5, 20.2, 20.1, 20.0. HR-MS (FAB) for C₁₉H₂₄N₂O₂Br: observ. 391.1017;theor. 391.1021.

Step 4: Hydrolysis of the Amide Function and Oxidation of the AlcoholFunction of the Hydroxyamide 1c Obtained in Step 3, to Obtain Compound1d

A solution of hydroxyamide 1c (445 mg, 1.2 mmol) in formic acid (85.0ml, 2.2 mol) is heated to reflux for 24 h. The solvent is evaporated ata reduced pressure, and the residue is taken up in 25 ml of distilledwater and then extracted with ethyl acetate (3×20 ml). The organicphases are combined, washed with a saturated sodium bicarbonate solution(2×20 ml), dried over anhydrous sodium sulphate, and then concentratedon a rotating evaporator. The oil obtained is taken up in methanolicammonia 7 N (85 ml, 3.8 mol). The reaction mixture is stirred in air atambient temperature for 3 days, and then it is concentrated at a reducedpressure. The residue is dissolved in methanol (30 ml) and 2 Mhydrochloric acid is added dropwise until pH=1. The reaction mixture ispurified by chromatography in a silica gel column (eluent:dichloromethane/methanol gradient: from 100/0 to 80/20), yielding 312 mg(85%) of the ketoacid 1d in the form of a yellow solid.

P_(f): 222° C. IR (KBr, cm⁻¹): 3419, 3067, 2923, 2852, 1703, 1679, 1605,1260, 669. NMR ¹H (300 MHz, DMSO-d6) δ (ppm): 9.11 (s, 1H), 8.68 (d,1H), 8.25 (s, 1H), 7.75 (d, 1H), 7.68 (s, 1H), 7.49 (d, 1H), 7.41 (t,1H), 7.26 (d, 1H). NMR ¹³C (75 MHz, DMSO-d6) δ (ppm): 194.8, 167.4,151.7, 150.9, 148.1, 139.8, 132.1, 122.2, 135.4, 131.2, 130.9, 128.0,120.7. HR-MS (ESI) for C₁₃H₇NO₃Br: observ. 303.9624; theor. 303.9609.

Step 5: Synthesis of Compound 1 by Cyclising the Compound 1d Obtained inStep 3

A solution of ketoacid 1d (331 mg, 1.1 mmol) in thionyl chloride (20.0ml, 300.0 mmol) is stirred at 60° C. in an inert atmosphere for 2 h. Thereaction medium is subsequently concentrated at a reduced pressure, andthe residue is taken up in dichloromethane and evaporated again. Thisoperation is repeated twice. The residue is finally taken up in acetone(17 ml), and then an aqueous 32% ammonium hydroxide solution (9.2 ml,3.0 mmol) is added dropwise. The resulting solution is stirred atambient temperature for 1 h. The reaction medium is concentrated on therotating evaporator. The residue obtained is purified by chromatographyin a silica gel column (eluent: dichloromethane/methanol gradient: from100/0 to 95/5), yielding 268 mg (80%) of the hemiamidal 1 in the form ofa beige powder.

P_(f): 211° C. IR (KBr, cm⁻¹): 3296, 3059, 1693, 1609, 1444, 1291, 647.NMR ¹H (500 MHz, DMSO-d6) δ (ppm): 9.53 (s, 1H), 8.89 (d, 1H), 8.75 (d,1H), 7.70 (t, 1H), 7.56 (ddd, 1H), 7.44 (m, 2H), 7.34 (t, 1H), 7.33 (s,1H). NMR ¹³C (126 MHz, DMSO-d6) δ (ppm): 167.5, 158.3, 153.6, 145.2,143.8, 122.2, 131.7, 131.2, 128.8, 126.5, 125.3, 118.3, 86.6. HR-MS(FAB) for C₁₃H₁₀N₂O₂Br: observ. 304.9927; theor. 304.9926.

EXAMPLE 1 Synthesis of Compound 2 of Formula

An alkylation reaction is carried out starting from compound 1, obtainedas described in Preparation 1 above.

n-dodecyl boronic acid (308 mg, 1.44 mmol), diphenylphosphino ferrocenepalladium (II) chloride (192 mg, 0.26 mmol), silver (I) oxide (760 mg,3.20 mmol) and potassium carbonate (542 mg, 4.00 mmol) are added to asolution of the hemiamidal 1 (400 mg, 1.32 mmol) in anhydroustetrahydrofuran (24 ml) in an inert atmosphere. The tube is hermeticallysealed and heated to 80° C. for 48 h. The solution is diluted indichloromethane (20 ml) and then an H₂O₂ (30%)/NaOH (10%) solution isadded. This is left for 2 h with stirring. The reaction mixture isextracted with dichloromethane (3×50 ml). The organic phases arecombined, dried over anhydrous sodium sulphate and concentrated in asilica gel column (eluent: dichloromethane/methanol gradient: from 100/0to 90/10), yielding 125 mg (24%) of the hemiamidal 2 in the form of anorange powder.

P_(f): 108° C. IR (KBr, cm⁻¹): 3478, 3413, 3064, 2925, 2851, 1706, 1615,1280. NMR ¹H (500 MHz, CDCl₃) δ (ppm): 8.82 (s, 1H), 8.62 (d, 1H), 7.40(s, 1H), 7.37-7.33 (m, 2H), 7.31-7.28 (m, 2H), 7.19 (d, 1H), 5.43 (slarge, 1H), 2.60 (t, 2H), 1.59 (q, 2H), 1.30-1.27 (m, 18H), 0.90 (t,3H). NMR ¹³C (126 MHz, CDCl₃) δ (ppm): 168.1, 158.3, 153.2, 145.4,144.0, 138.2, 129.3, 128.8, 125.6, 125.2, 122.7, 117.9, 88.1, 36.0,31.5, 32.0, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 22.7, 14.1. HR-MS(FAB) for C₂₅H₃₅N₂O₂: observ. 395.2712; theor. 395.2699.

EXAMPLE 2 Synthesis of Compound 3 of Formula

Step 1: Synthesis of Compound (3a)

Potassium carbonate (1.20 g, 8.70 mmol) is added to a solution of3-bromophenol (1.00 g, 5.78 mmol) in anhydrous dimethylformamide (60 ml)in an inert atmosphere at ambient temperature. After 5 minutes ofstirring, iododecane (2.57 g, 8.70 mmol) is added. After 18 h, thereaction mixture is filtered. The filtrate is diluted in water (15 ml)and extracted with ethyl acetate (3×30 ml). The organic phases arecombined, washed with a saturated sodium chloride solution, andconcentrated at a reduced pressure. The residue obtained is purified bychromatography in a silica gel column (eluent: hexane), yielding 1.86 g(94%) of the bromoether 3a in the form of a colourless oil.

IR (film, cm⁻¹): 3067, 2924, 2853, 1590, 1573, 1467, 1228, 680. NMR ¹H(250 MHz, CDCl₃) δ (ppm): 7.19-7.07 (m, 3H), 6.85 (dd, 1H), 3.96 (t,1H), 1.78 (q, 2H), 1.47-1.30 (m, 18H), 0.91 (t, 3H). NMR ¹³C (63 MHz,CDCl₃) δ (ppm): 160.0, 130.5, 123.5, 117.7, 113.6, 122.8, 68.3, 31.9,29.7-29.1, 26.0, 22.7, 14.1. MS (DCl/NH₃) m/z: 358-360 (M+NH₄), 340-342(M⁺).

Step 2: Synthesis of Compound 3 by Condensation of3,4-pyridinedicarboximide and the Compound 3a Obtained in Step 1

Tert-butyl lithium (7 ml, 10.5 mmol, 1.5 M in pentane) is added dropwiseto a solution of bromoether 3a (1.90 g, 5.57 mmol) in anhydroustetrahydrofuran (5.5 ml), in an inert atmosphere at −78° C. After 40minutes of stirring at −78° C., this solution is added dropwise to asolution of 3,4-pyridinedicarboximide (550 mg, 3.7 mmol) intetrahydrofuran (22 ml), in an inert atmosphere at −78° C. The reactionmixture is left to return to ambient temperature while stirring. 15 mlof water are added and the reaction mixture is extracted with ethylacetate (3×25 ml). The organic phases are combined, washed with asaturated aqueous sodium chloride solution (40 ml), dried over anhydroussodium sulphate and concentrated at a reduced pressure. The oily residueobtained is purified by chromatography in a silica gel column (eluent:dichloromethane/methanol gradient: from 100/0 to 90/10), yielding 346 mg(23%) of a para/meta (3/1) mixture of hemiamidal 3. The mixture isrecrystallised in acetone, yielding 3 in the form of a white powder (124mg, 8%).

P_(f): 131° C. IR (KBr, cm⁻¹): 3413, 3201, 3066, 2923, 2853, 1718, 1615,1260. NMR ¹H (500 MHz, DMSO-d6) δ (ppm): 9.46 (s, 1H), 8.86 (d, 1H),8.72 (d, 1H), 7.42 (dd, 1H), 7.26 (t, 1H), 7.15 (s, 1H), 7.06 (t, 1H),6.98 (dd, 1H), 6.89 (dd, 1H), 3.94 (t, 2H), 1.69 (q, 2H), 1.39 (m, 2H),1.30-1.25 (m, 16H), 0.86 (t, 3H). NMR ¹³C (126 MHz, DMSO-d6) δ (ppm):167.5, 159.1, 158.8, 153.4, 145.0, 142.7, 126.5, 131.9, 118.3, 118.0,114.5, 112.4, 87.6, 67.9, 31.7, 29.5-29.1, 22.5, 26.0, 14.4. HR-MS (ESI)for C₂₅H₃₅N₂O₃: observ. 411.2653; theor. 411.2648.

EXAMPLE 3 Synthesis of Compound 4 of Formula

Starting from compound 2, obtained as described in Example 1 above, areaction is carried out to quaternise the pyridine ring.

Ethyl bromoacetate (113 μl, 1.00 mmol) is added dropwise to a solutionof hemiamidal 2 (100 mg, 0.25 mmol) in anhydrous tetrahydrofuran (3.2ml) under reflux in an inert atmosphere. After 48 h, diethyl ether (10ml) is added, and the precipitate formed is filtered, washed with etherand dried in a vacuum, yielding 142 mg (78%) of the pyridinium salt 4 inthe form of a brown powder.

P_(f): Decomposition. IR (KBr, cm⁻¹): 3436, 3150, 2824, 2853, 1718,1655, 1437, 1217. NMR ¹H (500 MHz, DMSO-d6) δ (ppm): 10.27 (s, 1H), 9.54(s, 1H), 9.13 (d, 1H), 8.31 (d, 1H), 7.75 (s, 1H), 6.61 (s, 1H),7.36-7.34 (m, 2H), 7.25 (d, 1H), 5.69 (s, 2H), 3.79-3.78 (m, 2H), 2.58(t, 2H), 1.55 (m, 2H), 1.29-1.25 (m, 21H), 0.86 (t, 3H). NMR ¹³C (126MHz, DMSO-d6) δ ppm): 167.2, 166.3, 163.5, 164.5, 150.8, 143.6, 138.4,130.2, 129.6, 129.2, 126.1, 123.7, 122.3, 88.7, 60.9, 53.7, 35.7, 31.5,31.7, 29.6-29.2, 22.6, 14.4. HR-MS (ESI) for C₂₉H₄₁N₂O₄. observ.481.3039; theor. 481.3066.

EXAMPLE 4 Synthesis of Compound 5 of Formula

A reaction is carried out starting from compound 4, obtained asdescribed in Example 3 above, to reduce the pyridine ring.

A solution of sodium triacetoxyborohydride (12 mg, 0.053 mmol) in aceticacid (424 μl) is added to a solution of pyridinium salt 4 (20 mg, 0.036mmol) in ethanol (1.4 ml) in an inert atmosphere at 0° C. After 10 minof stirring, acetone (a few drops) is added, followed by water (10 ml),and the reaction mixture is extracted with dichloromethane (3×10 ml).The organic phases are combined, washed with a saturated sodiumbicarbonate solution (2×15 ml), dried over anhydrous sodium sulphate andconcentrated at a reduced pressure. The residue obtained is purified bychromatography in a silica gel column (eluent: dichloromethane/methanolgradient: from 100/0 to 90/10), yielding 5.6 mg (33%) of the1,4-dihydropyridine 5 in the form of an orangey-yellow oil.

NMR ¹H (300 MHz, CDCl₃) δ (ppm): 7.96 (m, 1H), 7.87 (s, 1H), 7.43-7.38(m, 2H), 7.13 (s, 1H), 5.89 (d, 1H), 5.29 (s large, 2H), 5.11 (d, 1H),4.91 (dd, 1H), 4.26 (q, 2H), 3.98 (s, 2H), 2.67 (t, 2H), 1.33 (t, 3H),1.29-1.25 (m, 20H), 0.90 (t, 3H). NMR ¹³C (126 MHz, CDCl₃) δ (ppm):198.8, 169.4, 168.9, 143.5, 138.4, 135.3, 133.4, 128.5, 129.7, 129.1,126.7, 102.8, 102.5, 61.8, 54.7, 44.1, 35.9, 31.9, 31.6, 29.7-29.3,22.7, 14.2, 14.1. HR-MS (ESI) for C₂₉H₄₃N₂O₄: observ. 483.3215; theor.483.3223.

EXAMPLES 5-7 Synthesis of1-(3-octyloxyphenyl)-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one(6),1-(2-dodecyloxyphenyl)-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one(7) and1-(3-octodecyloxyphenyl)-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one(8) Step 1: Synthesis of 1-bromo-3-octyloxybenzene (6a),1-bromo-2-decyloxybenzene (7a) and 1-bromo-3-octadecyloxybenzene (8a)

Potassium carbonate (1.2 g; 8.7 mmol) is added to a solution ofbromophenol (1.00 g; 5.8 mmol) in dimethylformamide (60 ml), the systemis left in an inert atmosphere for 5 minutes with stirring, andsubsequently 1-iodoalkane (8.67 mmol) is introduced. After 12 h ofreaction at ambient temperature, 40 ml of water are added, the reactionmedium is extracted with ethyl acetate (3×30 ml), the organic phases arerecovered, dried over anhydrous sodium sulphate and concentrated in avacuum. The residue obtained is purified by chromatography in a silicagel column (eluent: cyclohexane), yielding the desired compound.

Compound 6a: 87% IR (cm⁻¹): 3067, 2924 (CH), 2854, 1589 (C═C), 1466,1243, 1227 (C—O), 1028, 860, 762, 679 (C—Br). NMR ¹H (250 MHz, CDCl₃) δ(ppm): 7.20 (m, 3H); 6.90 (dt, J=1.4 Hz and 8.8 Hz, 1H); 3.90 (t, 2H,J=6.5 Hz); 1.87 (m, 2H); 1.53 (m, 10H); 0.99 (t, 3H, J=4.9 Hz). NMR ¹³C(63 MHz, CDCl₃) δ (ppm): 160.0 (C); 130.5 (CH); 123.6 (CH); 122.8 (C);117.8 (CH); 113.6 (CH); 68.3 (CH2); 31.9 (CH2); 29.4 (CH2); 29.3 (CH2);26.0 (CH2); 22.7 (CH2); 14.1 (CH3). MS (DCl/CH₄) m/z: 285/287 (M+H⁺).HR-MS: for C₁₄H₂₂OBr: theoretical mass: 285.0852; calculated mass:285.0854.

Compound 7a: 92% IR (cm⁻¹): 2922 (CH), 2853, 1588 (C═C), 1277, 1247(C—O), 1051, 1030, 744, 665 (C—Br). NMR ¹H (500 MHz, CDCl₃) δ (ppm):7.57 (dd, J=7.9 Hz and 1.6 Hz, 1H); 7.28 (ddd, J=1.6 Hz, 7.4 Hz and 7.4Hz, 1H); 6.91 (dd, J=1.4 Hz and 8.2 Hz, 1H); 6.84 (td, J=1.4 Hz and 7.7Hz, 1H); 4.05 (t, J=6.6 Hz, 2H); 1.87 (dt, J=6.6 Hz and 15.2 Hz, 2H);1.60-1.30 (m, 18H); 0.89 (t, J=6.2 Hz, 3H). NMR ¹³C (126 MHz, CDCl₃) δ(ppm): 155.5 (C); 133.3 (CH); 128.4 (CH); 121.6 (CH); 113.2 (CH); 112.3(C); 69.2 (CH2); 32.0 (CH2); 29.7-22.7 (9×CH2); 14.1 (CH3). MS (DCl/CH4)m/z: 342.4 (M+H⁺). HR-MS: for C₁₈H₃₀OBr: theoretical mass: 341.1464;calculated mass: 341.1480.

Compound 8a: 82% IR (cm⁻¹): 2915 (C—H), 2847, 1597 (C═C), 1471, 1241(C—O), 1021, 861, 782, 683 (C—Br). NMR ¹H (250 MHz, CDCl₃) δ (ppm): 7.18(m, 3H, H6); 6.87 (td, J=0.9 Hz, 1.4 Hz and 7.9 Hz, 1H); 3.98 (t, J=6.5Hz, 2H), 1.85 (t, J=6.5 Hz, 2H); 1.49 (m, 30H); 0.93 (t, J=6.1 Hz, 3H).NMR ¹³C (63 MHz, CDCl₃) δ (ppm): 160.0 (C); 130.5 (CH); 123.5 (CH);123.0 (C); 117.8 (CH); 113.5 (CH); 68.3 (CH2); 32.0 (CH2); 29.8-22.7(15×CH2); 14.1 (CH3). MS (DCl/CH4) m/z: 425.2/427.2 (M+H⁺). HR-MS: forC₂₄H₄₂OBr: theoretical mass: 425.2408; calculated mass: 425.2419.

Step 2: Synthesis of Compounds 6-8

1.5 M tert-butyllithium (1.5 ml; 2.42 mmol) is added dropwise to anappropriate, suitably substituted solution of bromoether obtained inaccordance with step 1 (1.21 mmol) in dry tetrahydrofuran (7.5 ml) in aninert atmosphere at −78° C. After this addition, the temperature isincreased to −50° C. for 30 minutes. The handling temperature is thenreduced to −78° C. again and this solution is added to3,4-pyridinedicarboximide (180 mg, 1.21 mmol) in anhydroustetrahydrofuran (12 ml) at −78° C. The reaction mixture is stirred forone hour at −50° C. Then, the reaction is treated with a saturatedammonium chloride solution (10 ml) and the reaction medium is extractedwith ethyl acetate (3×8 ml). The organic phases are recovered, driedover sodium sulphate and concentrated in a vacuum. The white powderobtained is purified by chromatography in a silica gel column (eluent:dichloromethane/methanol gradient: 100/0 to 93/7), yielding a mixture ofpara/meta compounds. The para product A is recovered cleanly after 3days of recrystallisation in acetone.

Compound 6: 28% IR (cm⁻¹): 3350 (NH, OH), 2918 (C—H), 2849, 1714 (C═O),1613 (C═C), 1465 (C—H), 1340, 1207, 1067, 727. NMR ¹H (500 MHz, MeOD) δ(ppm): 8.93 (s, 1H); 8.73 (d, J=5.0 Hz, 1H); 7.48 (dd, J=5.1 Hz and 0.8Hz, 2H); 7.29 (t, 1H, J=8.0 Hz); 7.18 (t, 1H, J=2.0 Hz); 7.07 (d, 1H,J=8.0 Hz); 6.91 (dd, J=7.5 and 1.8 Hz); 4.0 (m, 2H); 1.80 (q, J=6.5 Hz,2H); 1.49 (m, 18H); 0.93 (t, J=6.8 Hz, 3H). NMR ¹³C (126 MHz, MeOD) δ(ppm): 168.4 (C); 159.5 (CH); 159.4 (C); 152.5 (CH); 144.4 (CH); 141.0(C); 129.4, 117.2, 114.3, 111.6 (4×CH); 118.0 (C); 87.7 (C); 67.6 (CH2);31.5 (CH2); 29.0-28.9 (3×CH2); 25.7 (CH2); 22.2 (CH2); 13.0 (CH3).

Compound 7: 31% P_(f):=132° C. IR (cm⁻¹): 3199 (OH, NH), 3061 (C—H),2920, 2851, 1708 (C═O), 1619 (C═C), 1284, 1243, 1073, 1045, 1022. NMR ¹H(500 MHz, MeOD) δ (ppm): 8.90 (d, J=1.1 Hz, 1H); 8.69 (d, J=5.3 Hz, 1H);8.07 (dd, J=1.8 Hz and 7.8 Hz, 1H); 7.37 (ddd, J=1.8 Hz, 7.5 Hz and 8.1Hz); 7.32 (dd, J=1.4 Hz, and 5.1 Hz, 1H); 7.05 (dt, J=1.0 Hz and 7.7 Hz,1H); 6.88 (dd, J=0.7 Hz and 8.3 Hz, 1H); 3.74 (dt, J=6.3 Hz and 9.2 Hz,1H); 3.56 (dt, J=6.3 Hz and 9.1 Hz, 1H); 1.35-1.20 (m, 18H); 0.92 (t,J=6.8 Hz, 3H). NMR ¹³C (126 MHz, MeOD) δ (ppm): 169.1 (C); 160.5 (C);155.9 (C); 152.1 (CH); 143.8 (CH); 130.2 (CH); 128.5 (C); 127.8 (CH);125.8 (CH); 119.8 (CH); 117.3 (CH); 111.6 (CH); 85.6 (C); 67.8 (CH2);31.7-25.6 (9×CH2); 22.4 (CH2); 13.1 (CH3). MS (ESI/CH₃OH)): 433 (M+Na⁺);411 (M+H⁺); 393 (M+H⁺—H₂O). HR-MS: for C₂₅H₃₅N₂O₃: theoretical mass:411.2681; calculated mass: 411.2648.

Compound 8: 23% P_(f): 113° C. IR (cm⁻¹): 3141 (NH, OH), 3059, 2920(C—H), 2851, 1708 (C═O), 1607 (C═C), 1578, 1286, 1258, 1030, 700. NMR ¹H(500 MHz, MeOD) δ (ppm): 8.93 (s, 1H); 8.73 (d, J=5.4 Hz, 1H); 7.46 (d,J=0.95 Hz and 5.1 Hz, 1H); 7.29 (t, J=8.0 Hz, 1H); 7.17 (m, 1H); 7.08(dd, J=8.8 Hz and 1.7 Hz, 1H); 6.91 (dt, J=8.3 Hz, other J notmeasurable, 1H); 3.99 (m, 2H); 1.78 (q, J=6.7 Hz, 2H); 1.48-1.31 (m,30H); 0.92 (t, J=6.8 Hz, 3H). NMR ¹³C (125 MHz, MeOD) δ (ppm): 1quaternary carbon absent, 168.5 (C); 159.5 (C); 159.4 (C); 152.6 (CH);144.5 (C); 141.1 (C); 129.4 (CH), 126.4 (C); 117.9 (CH), 117.4 (C),114.5 (CH); 111.8 (CH); 67.9 (C); 31.6 (CH2); 29.3-28.9 (13×CH2); 25.7(CH2); 22.2 (CH2); 12.9 (CH3). MS (ESI/CH₃OH)): 495.5 (M+H⁺). HR-MS: forO₃₁H₄₇N₂O₃: theoretical mass: 495.3618; calculated mass: 495.3587.

EXAMPLE 8 Synthesis of1-[3-(dodecylthio)phenyl]-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one(9)

Step 1: Synthesis of 1-bromo-3-(dodecylthio)benzene (9a)

Potassium carbonate (1.6 g; 11.8 mmol) is added to a solution of3-bromobenzene thiol (1.50 g; 7.9 mmol) in dimethylformamide (90 ml) andthe system is left in an inert atmosphere for 5 minutes with stirring,and subsequently 1-iododecane (3.5 g; 11.8 mmol) is introduced. After 16h of reaction at ambient temperature, 50 ml of water are added, thereaction medium is extracted with ethyl acetate (3×30 ml), and theorganic phases are recovered, dried over sodium sulphate andconcentrated in a vacuum. The product obtained 9a, in the form of acolourless oil (4.5 g), is purified by chromatography in a silica gelcolumn (eluent: cyclohexane), yielding 1.9 g (70%).

IR (cm⁻¹): 2921 (C—H), 2851 (C—H), 1576 (C═C), 1458 (C—S), 1068, 753,676 (C—Br); NMR ¹H (250 MHz, CDCl₃) δ (ppm): 7.46 (dd, 1H, J=6.7 Hz and1.6 Hz); 7.23-7.32 (m, 2H, H4); 7.16 (dd, 1H, J=12.0 Hz and 7.8 Hz);2.97 (t, 2H, J=7.2 Hz); 1.65 (t, 2H, J=7.3 Hz); 1.29 (m, 18H); 0.91 (t,J=6.6 Hz, 3H). NMR ¹³C (63 MHz, CDCl₃) δ (ppm): 139.8 (C); 130.7 (CH);130.0 (CH); 128.5 (CH); 126.9 (C); 122.8 (C); 33.3 (CH2); 31.9 (CH2);29.7-28.8 (8×CH2); 22.7 (CH2); 14.1 (CH3). MS (DCl/CH₄) m/z: 357 (M+H⁺);385 (M+C₂H₅ ⁺). HR-MS: for C₁₈H₃₀SBr: theoretical mass: 357.1236;calculated mass: 357.1252.

Step 2: Synthesis of Compound (9)

n-butyllithium 1.5 M (1.4 ml; 3.36 mmol) is added dropwise to a solutionof bromobenzene 9a (1.00 g; 2.8 mmol) in dry tetrahydrofuran (18 ml) inan inert atmosphere at −78° C. After this addition, the temperature isincreased to −50° C. for 30 minutes. The handling temperature is thenreduced to −78° C. again and this solution is added to3,4-pyridinedicarboximide (166 mg, 1.12 mmol) in anhydroustetrahydrofuran (22 ml). The reaction mixture is stirred for one hour at−50° C. Then, the reaction is treated with a saturated ammonium chloridesolution (30 ml) and the reaction medium is extracted with ethyl acetate(3×20 ml). The organic phases are recovered, dried over sodium sulphateand concentrated in a vacuum. The white powder obtained (720 mg) ispurified by chromatography in a silica gel column (eluent:dichloromethane/methanol gradient: 100/0 to 93/7), yielding 128 mg (48%)of the para/meta mixture of compounds. The para product is recovered(32.3 mg; 28%) after 3 days of recrystallisation in acetone. Thisrecrystallisation product is still contaminated with 23% meta compound.

P_(f):=86° C. IR (cm⁻¹): 3159 (NH, OH), 2917 (C—H), 2848 (C—H), 2424,1698 (C═O), 1614 (C═C), 1547, 1464 (C—S), 1347, 1067, 964 (C═C), 784,698. NMR ¹H (250 MHz, MeOD) δ (ppm): 8.94 (s, 1H); 8.74 (d, 1H, J=5.0Hz); 7.56 (s, 1H); 7.46 (d, 1H, J=4.6 Hz, 1H); 7.31 (m, 3H, H14); 2.96(t, 2H, J=7.0 Hz); 1.64 (m, 2H); 1.42 (m, 18H); 0.94 (t, 3H, J=6.0 Hz).NMR ¹³C (126 MHz, MeOD) δ (ppm): 159.0 (C); 152.7 (CH); 150.0 (C); 144.4(CH); 144.0 (C); 140.0 (C); 138.0 (C); 128.9 (CH), 128.4 (CH); 125.2(CH), 122.5 (CH); 118.0 (CH, C5); 88.0 (C), 71.0 (CH2); 32.6 (CH2); 31.7(CH2); 29.4-28.4 (CH2); 22.3 (CH2); 13.0 (CH3, C29).

MS (ESI/CH₃OH)): 449.2 (M+Na⁺); 427.3 (M+H⁺). HR-MS: for C₂₅H₃₅N₂O₂S:theoretical mass: 411.2681; calculated mass: 411.2648.

EXAMPLE 9 Synthesis of1-(3-dodecyloxyphenyl)-1-methoxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one(10)

0.5 ml of thionyl chloride are added to a solution of 3 (100 mg; 0.44mmol) in methanol dried on a molecular sieve (6 ml). The mixture isbrought to reflux in an argon atmosphere for 16 h. The heating ishalted, and when the medium reaches ambient temperature, it is treatedwith a saturated sodium bicarbonate solution (5 ml) and extracted withethyl acetate (3×8 ml). The organic phases are recovered, dried oversodium sulphate and concentrated in a vacuum, yielding 93 mg (89%)yellow oil.

IR (cm⁻¹): 2922 (C—H), 2852, 1726 (C═O), 1603 (C═C), 1438, 1287 (C—O),1051, 698.

NMR ¹H (250 MHz, CDCl₃) δ (ppm): 9.08 (s, 1H), 8.78 (s, 1H), 7.39-6.89(m, 6H), 3.97 (t, J=6.4 Hz, 2H), 3.17 (s, 3H), 1.79 (t, J=5.5 Hz, 2H),1.45-1.28 (m, 18H), 0.91 (t, J=5.9 Hz, 3H). NMR ¹³C (63 MHz, CDCl₃) δ(ppm): 168.1 (C); 159.6 (CH); 154.9 (C); 153.2 (CH); 146.0 (CH); 139.7(2×C); 130.0 (CH), 118.0 (C) 117.4 (CH), 114.8 (CH); 112.1 (CH); 91.9(C); 68.2 (CH2); 50.9 (CH3); 31.9 (CH2); 29.6-29.3 (6×CH2); 26.0 (CH2);22.7 (CH2), 14.1 (CH2); 1.0 (CH3). MS (ESI/CH₃OH)) m/z: 425.6 (M+H⁺).HR-MS: for C₂₆H₃₇N₂O₃: theoretical mass: 425.2847; calculated mass:425.2804.

The following compounds were synthesised by applying or adapting methodsdisclosed above using appropriate starting materials and reagents:

Ex.

R1 R2 R3 1

together form a single bond OH 2

together form a single bond OH 3

together form a single bond OH 4

H together form a * ═O group 5

together form a single bond OH 6

together form a single bond OH 7

together form a single bond OH 8

together form a single bond OH 9

together form a single bond OCH₃ 10

together form a single bond OH 11

together form a single bond OH 12

together form a single bond OH 13

together form a single bond OH 14

together form a single bond OH 15

together form a single bond OH 16

H together form a * ═O group 17

H together form a * ═O group

In the table above, the asterisks (*) denote the positions ofattachments and substitutions of the rings A and B.

EXAMPLE 18 Demonstration of the Inhibitory Effect of the ClaimedCompounds on InhA Activity 1—Preparation of InhA Enoylreductase

The InhA protein was expressed in E. coli after cloning the inhA gene ina plasmidic vector of the pET type. Growing the resulting strain andinducing expression of the inhA gene with 1 mM IPTG (isopropylβ-D-thiogalactoside) leads to the production of water-soluble InhAprotein at approximately 28.5 KDa (28,368 Da) (monomeric) which ispurified by standard protein purification techniques. The enzyme ispresent in the form of a tetramer in solution and is kept in 50 mM Hepesbuffer, 50% glycerol at −20° C.

2—Evaluation of the Activity of InhA Enoylreductase

The InhA enoylreductase activity is monitored by UV spectrometry, bymonitoring the disappearance of the signal of the reduced cofactor NADHat 340 nm as a function of time. The percentage inhibition is calculatedby subtracting from 100 the ratio of the initial speeds (V) measuredduring kinetics with and without inhibitor, multiplied by 100:%inhibition=100−(V_(inhib)/V_(blank)*100). The initial speed is measuredby drawing the tangent to the curve DO=f(time) at time zero.

3—InhA Enoylreductase Activity Inhibition Test

The enzymatic reaction is carried out in a final volume of 100 μl (in aquartz vessel, optical path 1 cm). The absorption of each reactionmixture is determined with a UVIKON 293 spectrophotometer (Bio-TekKontron Instruments) connected to a thermostatically controlled bathwhich makes it possible to maintain the temperature of the vessel at 25°C. A baseline is produced during preincubation immediately beforemeasurements begin. The measurements are carried out over 3 min after apreincubation of 5 min or 2 h.

The preincubation is carried out in 90 μl (total volume) of a solutionof PIPES buffer 30 mM, NaCl 150 mM, pH=6.8 at 25° C. containing 100 nMof InhA, 100 μM, 20 μM or 10 μM of the compound to be tested (or 500 nMof the pool of INH-NAD adducts constituting the control inhibitors) and200 μM of NADH. After 5 min or 2 h of preincubation, the addition of 35μM of the substrate 2-trans-decenoyl-CoA initiates the reaction.Alternatively, the preincubation is carried out in 80 μl (total volume)of a solution of PIPES buffer 30 mM, NaCl 150 mM, pH=6.8 at 25° C.containing 100 nM of InhA and 100 μM, 20 μM or 10 μM of the compound tobe tested (or 500 nM of the pool of adducts constituting the controlinhibitors). After 5 min or 2 h of preincubation, the addition of 200 μMof NADH and 35 μM of 2-trans-decenoyl-CoA initiates the reaction.

4—Results

The results obtained show that some derivatives of the molecular familyaccording to the invention exhibit an efficacious inhibitory effect onthe operation of InhA, close to that of the active metabolites ofisoniazide (obtained by biomimetic synthesis in the form of a mixture ofadducts). The InhA inhibition percentages as a function of the inhibitorconcentration and for a preincubation time of 5 min (or *2 h) are shownbelow:

Reference mixture of INH-NAD adducts: 10 μM 92% Compound of example 2100 μM 41% (* 80%) 100 μM 91% Compound of example 3 10 μM 19% Compoundof example 4 10 μM 25%

EXAMPLE 19 Demonstration of the Growth Inhibition of the CompoundsAccording to the Invention on Different Bacterial Strains: Case ofMycobacterium smegmatis

1—Preparation of the Bacterial Suspension of Mycobacterium smegmatis

The strain Mycobacterium smegmatis mc²155 (R₀) is cultivated in aculture medium of Middelbrook 7H9(Difco)+glycerol 0.2%+0.05% Tween 80 at37° C. with stirring (200 rpm) to avoid the formation of a bacterialfilm. After 3 days, the R₀ culture is left to rest for 10 min, in whichtime the largest aggregates settle. The supernatant is removed to starta new culture R₁, in the same conditions, seeded at 1/100. After 3 daysof stirring at 37° C. and 10 min of rest, the supernatant is removed.The optical density of the bacterial suspension is measured at 650 nmand set to a value of between 0.002 and 0.003 by dilution in the culturemedium (without Tween 80), and this is R₂.

2—Evaluation of the Growth of the Bacterial Suspension of Mycobacteriumsmegmatis

The antimycobacterial activity is evaluated by MTT reductioncolorimetric tests(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) onthe strain M. smegmatis mc²155. Once the bacteria have been allowed todevelop normally, the yellow tetrazolium salt (MTT) is reduced andchanges colour, becoming purple. By contrast, if the growth of thebacteria is completely inhibited by one of our compounds, the reductioncannot take place and the solution remains yellow. Reading the opticaldensity at 570 nm makes it possible to observe the formation of purple,reduced MTT fromazan The percentage inhibition is calculated bysubtracting from 100 the ratio of the DO measured with and withoutinhibitor, multiplied by 100: 100−(DO_(inh.)/DO_(tem)*100).

3—Inhibitive Activity of the Products to be Tested on the Growth of theBacterial Suspension of Mycobacterium smegmatis

The tests are carried out on 96-well NUNC microplates (Merk-eurolab).Each product is tested over a concentration range starting at 5 mM bycarrying out successive dilutions of two by two. Each well contains 100μl of compound in solution in the culture medium (7H9+0.2% Gro with 1%(v/v) final DMSO). Subsequently, 100 μl of bacterial suspension R₂ areadded. The plate is sealed using parafilm and incubated at 37° C. After24 hours of incubation, 50 μl of a 1 mg/ml solution of MTT are added toeach well. After 3 hours of incubation at 37° C., 100 μl of lysis bufferare added to each well and the plate is left with stirring at ambienttemperature until the solution is fully homogeneous.

The optical density is measured at 570 nm with a μQuant microplatespectrophotometer, Bio-tek Instruments, Inc.

4—Results

The results obtained show that some derivatives of the family accordingto the invention exhibit CI₅₀ values (concentration corresponding to 50%inhibition) on the growth of the strain Mycobacterium smegmatis whichare better than those observed for the isoniazide used as a reference.

EXAMPLE 19 Demonstration of the Growth Inhibition of the CompoundsAccording to the Invention on Different Bacterial Strains: Case ofCorynebacterium qlutamicum

The CI₅₀ of the compounds according to the invention on the bacterialstrain C. glutamicum and for the control INH was determined.

As expected, INH does not exhibit any activity on C. glutamicum at 5 mM.

The compounds according to the invention, specifically describedhereinafter, are able to inhibit the growth of the bacterium C.glutamicum at a CI₅₀ less than or equal to 10 μM. These results suggestthat the compounds cited below have another molecular target in additionto InhA.

In fact, the bacteria in this strain exhibit the distinctive feature ofnot having a FAS-II elongation cycle in the biosynthesis of fatty acids.There is no InhA equivalent in C. glutamicum. The compounds according tothe invention which act on this strain of bacteria therefore also have atarget other than the FASS-II system.

Preparation of the Bacterial Suspension of C. glutamicum

The Corynebacterium glutamicum strain is cultivated in a BHI(Brain-Heart Infusion) medium at 30° C. with stirring at 200 rpm. The DOof the culture is measured directly and set to a value of 0.002-0.003 bydilution in the LB culture medium. C. glutamicum also grows in the LBmedium, and this is used instead of BHI, which is strongly coloured andinterferes with the DO reading at 570 nm.

Preparation of the Solutions of Compounds to be Tested

The concentration ranges tested on C. glutamicum are shown in the table.

Compounds Concentration range tested INH  5 mM to 2.4 μM A 156 μM to 2.4μM  Example 2 312 μM to 4.9 μM  Example 4 78 μM to 1.2 μM Example 5 39μM to 0.6 μM

The stock solutions are prepared in DMSO at a concentration 100 timesgreater than the highest concentration to be tested.

Evaluation of the Growth of the Bacterial Suspension of C. glutamicum

The test is carried out in the same way as the test on M. smegmatis.

The tests are carried out on 96-well NUNC microplates (Merck-eurolab).All the concentrations were tested at least twice.

Each well contains 100 μl of compound in solution in the culture medium(LB with 1% final DMSO). Subsequently, 100 μl of bacterial suspensionhaving DO 0.002 at 650 nm are added.

The plate is sealed using parafilm and incubated at 30° C. for C.glutamicum. After two hours of incubation, 50 μl of a 1 mg/ml solutionof tetrazolium salt (MTT) are added to each well. After one hour ofincubation at 30° C. for C. glutamicum, 100 μl of lysis buffer are addedto each well and the plate is left with stirring at ambient temperatureuntil the solution is fully homogeneous.

The optical density is measured at 570 nm with a μQuant 96-wellmicroplate spectrophotometer, Bio-tek Instruments, Inc.

Results

The CI₅₀ values of isoniazide and 4 compounds on the bacterial strainCoryne glutamicum are shown below:

Compound A: Example 2: Example 4:

EXAMPLE 5 Isoniazide CI₅₀>5 mM

The results obtained demonstrate the ability of the compounds accordingto the invention to inhibit the growth of C. glutamicum (a bacterialstrain without an InhA equivalent), and this suggests that other targetsmay exist.

1. Compounds of general formula (I):

in which: the cycle

represents a 6-membered aromatic or non-aromatic ring, optionallycomprising one or more nitrogen atoms, said nitrogen atom(s) optionallybeing substituted by an optionally substituted tetrahydrofuran group,such as 2-hydroxymethyl-tetrahydrofuran-3,4-diol; or by a —CH₂-E group,wherein E represents an electron-attracting group such as —CONRR′;—CO—SR; —CO—Oalkyl; —CO—Oalkyl-OH; —O-alkyl-OAc; phenyl substituted forexample by a CN or NO₂ group; wherein R and R′ are the same or differentand independently represent a hydrogen atom or an alkyl group; and/orwherein said nitrogen atom(s) may be in the form of pyridinium salts,the counter ion being the anion of a halogen atom, such as bromide;

represents a 5-to-10-membered mono- or bicyclic aryl or heteroarylgroup, substituted by one or more groups selected from the groups —OH;—(C₅-C₂₀)alkyl; —Oalkyl; —S(O)_(p)alkyl wherein p=0, 1 or 2; alkenyl;alkynyl; —Oalkenyl; —C(═)O-alkyl; —C(═O)-alkenyl; phenyl substituted byan alkyl group; cycloalkyl optionally substituted by an alkyl group; R1represents a hydrogen atom or an alkyl group and R2 and R3 together forman ═O group; or alternatively R3 represents an —OH or —Oalkyl group andR2 forms, together with R1, a single bond binding the nitrogen atom tothe carbon atom substituted by R3,

in such a way as to form an indanone ring by fusion with the cycle

the groups —C(═O)NHR1 and C(R3)(R2)- being understood to be located intwo adjacent positions on the ring

in the form of a base or an acid addition salt, as well as in the formof a pharmaceutically acceptable hydrate or solvate.
 2. Compoundsaccording to claim 1, wherein in the general formula (I),

is a phenyl, pyridine, pyrazine or dihydropyridine ring.
 3. Compoundsaccording to claim 1, wherein in the general formula (I),

represents a dihydropyridine or pyridine group, optionally substitutedby a group selected from the groups —CH₂—CO—Oalkyl; —CH₂—CO—Oalkyl-OH;—CH₂—O-alkyl-OAc, and/or optionally in the form of a pyridinium halide.4. Compounds according to claim 1, wherein in the general formula (I),

is a phenyl ring substituted by a —OH, (C₅-C₂₀)alkyl, O(C₅-C₂₀)alkenyl,O(C₅-C₂₀)alkyl or —S(O)_(p)alkyl group wherein p=0, 1 or
 2. 5. Compoundsaccording to claim 1, wherein in the general formula (I),

is substituted in the ortho or meta position.
 6. Compounds according toclaim 1, wherein in the general formula (I), R3=OH or —Oalkyl and R1 andR2 together form a single bond.
 7. Compounds according to claim 1,wherein in the general formula (I), R3 and R2 form an ═O group and R1represents a hydrogen atom.
 8. Compounds according to claim 1, whereinin the general formula (I):

represents a dihydropyridine group, optionally substituted by a groupselected from —CH₂COOalkyl, —CH₂COOalkylOH;

represents a phenyl group, substituted in the meta position, by a groupselected from the groups C₅-C₂₀ alkyl, —Oalkyl, —Oalkenyl, —OH, phenyloptionally substituted by alkyl; R1 and R2 together form a single bondand R3=OH, or R1=H and R2 and R3 together form an ═O group; in the formof a base or an acid addition salt, as well as in the form of apharmaceutically acceptable hydrate or solvate.
 9. Compounds accordingto claim 1, selected from the following compounds:1-(3-dodecylphenyl)-1-hydroxy-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;1-(3-dodecyloxyphenyl)-1-hydroxy-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;1-(3-dodecylphenyl)-5-[2-(ethyloxy)-2-oxoethyl]-1-hydroxy-3-oxo-1,2-dihydropyrrolo[3,4-c]pyridiniumbromide; ethyl3-aminocarbonyl-[4-(3-dodecylbenzoyl)-1,4-dihydro-pyridin-1-yl]acetate;1-(3-octyloxyphenyl)-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;1-(2-dodecyloxyphenyl)-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;1-(3-octodecyloxyphenyl)-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;1-[3-(dodecylthio)phenyl]-1-hydroxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;1-(3-dodecyloxyphenyl)-1-methoxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;1-hydroxy-1-(3-(propen-3-yl)oxyphenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;1-hydroxy-1-(3-hydroxyphenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;1-hydroxy-1-(3-octylphenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;1-hydroxy-1-(3-(4-nonylphenyl)phenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;1-[3-(dodecyloxy)phenyl]-5-(2-ethoxy-2-oxoethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-5-iumbromide;1-[(3-(dodecyloxy)phenyl)-1-hydroxy-5-[2-(3-hydroxypropoxy)-2-oxyethyl]-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-5-iumbromide; ethyl3-aminocarbonyl-[4-(3-dodecyloxybenzoyl)-1,4-dihydropyridin-1-yl]acetate;3-hydroxypropyl3-aminocarbonyl-[4-(3-dodecyloxybenzoyl)-1,4-dihydropyridin-1-yl]acetate;in the form of a base or an acid addition salt, as well as in the formof a pharmaceutically acceptable hydrate or solvate.
 10. Method for thepreparation of a compound of general formula (I) according to claim 1 inwhich R1 and R2 together form a single bond and R3 represents —OH,comprising the step of coupling a compound of general formula (II):

and a compound of general formula (III):

resulting in a compound of formula (IV):

in which

and R1 are defined as in general formula (I), Hal represents a halogenatom and X represents a hydrogen atom, when

is not substituted, or the substituent of

corresponding to the desired general formula (I) (in these two cases,the compound (IV) corresponds to the compound (I)), or a halogen atom,the coupling being followed in this case by the reaction substitutingthe halogen atom of the compound (IV) with the appropriate substituentof

corresponding to the desired general formula (I).
 11. Method for thepreparation of a compound of general formula (I) according to claim 1 inwhich R1 and R2 together form a single bond and R3 represents —OH,comprising the step of cyclising compounds of general formula (V):

in which

and Hal are defined as in general formula (IV) in the presence of NHR1(V′), resulting in the compound of formula (IV):

in which R1 is defined as in general formula (I) and X represents ahydrogen atom, when

is not substituted, or the substituent of

corresponding to the desired general formula (I) (in these two cases,the compound (IV) corresponds to the compound (I)), or a halogen atom,the cyclisation being followed in this case by the reaction substitutingthe halogen atom of the compound (IV) with the appropriate substituentof

corresponding to the desired general formula (I).
 12. Method accordingto claim 10 for the preparation of a compound of general formula (I) inwhich

represents a pyridinium ring in which the nitrogen atom is quaternised,the preparation method further comprising the subsequent step ofquaternising the compound of general formula (I) in which

represents a pyridine ring using a compound of general formula (XII):R-Hal  (XII) in which Hal represents a halogen atom and R represents agroup of the —CH₂E type, E being an electron-attracting group as definedin claim
 1. 13. Method for the preparation of a compound of generalformula (I) in which

represents a dihydropyridine ring and R2 and R3 together form an ═Ogroup and R1 represents a hydrogen atom, said method comprising themethod according to claim 12 followed by the step of reducing thecompound of general formula (I) in which

represents a pyridinium ring.
 14. Method according to claim 10, furthercomprising the reaction to isolate and/or purify the obtained product.15. Pharmaceutical composition comprising as an active ingredient acompound of general formula (I):

in which: the cycle

represents a 6-membered aromatic or non-aromatic ring, optionallycomprising one or more nitrogen atoms, said nitrogen atom(s) optionallybeing substituted by an optionally substituted tetrahydrofuran group,such as 2-hydroxymethyl-tetrahydrofuran-3,4-diol; or by a —CH₂-E group,wherein E represents an electron-attracting group such as —CONRR′;—CO—SR; —CO—Oalkyl; —CO—Oalkyl-OH; —O-alkyl-OAc; phenyl substituted forexample by a CN or NO₂ group; wherein R and R′ are the same or differentand independently represent a hydrogen atom or an alkyl group; and/orwherein said nitrogen atom(s) may be in the form of pyridinium salts,the counter ion being the anion of a halogen atom, such as bromide;

represents a 5-to-10-membered mono- or bicyclic aryl or heteroarylgroup, substituted by one or more groups selected from the groups —OH;—(C₅-C₂₀)alkyl; —Oalkyl; —S(O)_(p)alkyl wherein p=0, 1 or 2; alkenyl;alkynyl; —Oalkenyl; —C(═)O-alkyl; —C(═O)-alkenyl; phenyl optionallysubstituted by an alkyl group; cycloalkyl optionally substituted by analkyl group; R1 represents a hydrogen atom or an alkyl group and R2 andR3 together form an ═O group; or alternatively R3 represents an —OH or—Oalkyl group and R2 forms, together with R1, a single bond binding thenitrogen atom to the carbon atom substituted by R3,

in such a way as to form an indanone ring by fusion with the cycle

the groups —C(═O)NHR1 and C(R3)(R2)- being understood to be located intwo adjacent positions on the ring

in the form of a base or an acid addition salt, as well as in the formof a pharmaceutically acceptable hydrate or solvate; and at least onepharmaceutically acceptable excipient.
 16. Combination of a compound ofgeneral formula (I) according to claim 1 and an anti-infective activeingredient.
 17. Use of a compound according to claim 1 for thepreparation of an anti-infective drug.
 18. Compound of general formula(I) according to claim 1 for the treatment and/or prevention ofinfections.
 19. Compound according to claim 18, wherein said human oranimal infections are selected from mycobacterioses, such astuberculosis, leprosy or opportunistic diseases, such as those caused byMycobacterium avium, M. bovis and/or M. ulcerans, M. marinum; malaria,or any infection caused by a pathogen having an enzyme of the enoyl acylcarrier protein reductase type or an enzyme of a related structurebelonging to the short chain dehydrogenase reductase (SDR) superfamily.20. Compound according to claim 19 for the treatment and/or preventionof tuberculosis.